Desogestrel and Etonogestrel are used in third-generation contraceptive formulations particularly useful for the administration to subjects suffering from diabetes or lipid disorder, due to their minimal impact on glucose levels in blood and lipid profile. Furthermore, Desogestrel and Etonogestrel can be used at lower estrogen doses than second-generation contraceptives, reducing the likelihood of weight increase, mastodynia and migraine.
The synthesis of Desogestrel and Etonogestrel is generally carried out from the intermediate compound 11-methylene-18-methyl-estr-4-en-3,17-dione having the above-depicted formula (I). For example, the preparation of Etonogestrel from compound (I) is described in article “Synthesis of 13-ethyl-17-hydroxy-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3-one (3-oxo desogestrel)”, H. Gao et al., STEROIDS, 1997, 62(5), 398-402; the synthesis of Desogestrel from compound (I) is described in article “A partial synthesis of 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol (desogestrel) based upon intramolecular oxidation of an 11β-hydroxy-19-norsteroid to the 18→11β-lactone”, M. J. van den Heuvel et al., Recueil des Travaux Chimiques des Pays-Bas, 107/4, 331-334 (1988).
The synthesis of 11-methylene-18-methyl-estr-4-en-3,17-dione is known from various patent and scientific literature documents.
The first document that describes the synthesis of compound (I) is U.S. Pat. No. 3,927,046 (1975). This synthesis uses 11α-hydroxy-18-methyl-estra-4-en-3,17-dione as starting product, which can be obtained from 3,17-diketo-18-methyl-estra-4-ene by hydroxylation in position 11α with Aspergillus Ochraceus; 11α-hydroxy-18-methyl-estra-4-en-3,17-dione is reacted with ethylene glycol, thus protecting the two ketone groups as acetals.
However, the synthesis described in this patent has some drawbacks.
Firstly, this synthesis results in a complex mixture of products due to both the migration of the double bond from positions 4(5) to positions 5(10) and 5(6), and to the configuration instability caused by the hydroxyl in 11α, as also noted in Tetrahedron 50(36), 10709-10720, 1994. This complex mixture of products, consisting of double bond isomers and of structural stereoisomers of the backbone, can be separated by sophisticated chromatography methods only with long and complex laboratory procedures, which makes this synthesis absolutely not applicable to prepare a product in such amounts to make it suitable for industrial development.
Another drawback of the synthesis in U.S. Pat. No. 3,927,046 is that among its steps, it comprises the oxidation of 11α-hydroxy-18-methylestr-5-en-3,17-dione-3,17-diethylene ketal to 18-methylestr-5-en-3,11,17-trione-3,17-diethylene ketal with the mixture CrO3-sulfuric acid (Jones reagent); the use of a chromium reagent (VI), which is a recognized carcinogen, makes this synthesis not applicable to a large-scale production.
Finally, the methylene function in position 11 is introduced on 18-methylestr-5-en-3,11,17-trione-3,17-diethylene ketal through the triphenylphosphonium bromide ylide (Wittig reaction) and continues with the acid hydrolysis of the two acetals, thus obtaining the desired product; as an alternative, the oxidation of 11α-hydroxy-18-methyl-estra-4-en-3,17-dione to 18-methyl-estra-4-en-3,11,17-trione is carried out, followed by selective protection of carbonyls in position 3 and 17 as ketals. However, these methods do not have a synthetic utility at a practical level, as also noted in article “Selective Ketalization of Steroidal 3,11,17-Trione using Chlorotrimethylsilane as Catalyst”, X. Su of al., Synthetic communications 25(18), 2807-2811 (1995).
On the other hand, also the preparation described in the same article by X. Su et al. also gives a 70% yield, with product recovery by silica gel chromatography at low pressure, and chromatography is a technique with a poor industrial utility as well.
Totally different syntheses, such as for example the one described in article “A short enantioselective total synthesis of the third-generation oral contraceptive Desogestrel”, E. J. Corey et al., J. Am. Che. Soc. vol. 121(4) 710-714, 1999, where the steroid backbone is constructed, certainly have a scientific value but do not seem industrially applicable; a reason is that in order to obtain 17α-hydroxy-11-methylene-18-methylestr-4-en-3-one, at least 13 synthetic steps are required, which add up to the step required for the oxidation of position 17.
A similar drawback—the excessive number of reactions required—can also be found in the synthesis described in patent application CN 1865276 which, while starting from the steroid backbone already completed, requires 11 reaction steps to obtain 11-methylene-18-methylestr-4-en-3,17-dione.